NO330859B1 - Process for the esterification of carbothiotic acid - Google Patents
Process for the esterification of carbothiotic acid Download PDFInfo
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- NO330859B1 NO330859B1 NO20071996A NO20071996A NO330859B1 NO 330859 B1 NO330859 B1 NO 330859B1 NO 20071996 A NO20071996 A NO 20071996A NO 20071996 A NO20071996 A NO 20071996A NO 330859 B1 NO330859 B1 NO 330859B1
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- pyridine
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- 238000000034 method Methods 0.000 title claims abstract description 48
- 239000002253 acid Substances 0.000 title claims description 27
- 238000005886 esterification reaction Methods 0.000 title claims description 11
- 230000032050 esterification Effects 0.000 title claims description 8
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 28
- 150000001875 compounds Chemical class 0.000 claims description 68
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- 238000004519 manufacturing process Methods 0.000 claims description 15
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- 150000003512 tertiary amines Chemical class 0.000 claims description 12
- 150000001263 acyl chlorides Chemical class 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
- 239000012442 inert solvent Substances 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 229960000289 fluticasone propionate Drugs 0.000 claims description 9
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 claims description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- ITQTTZVARXURQS-UHFFFAOYSA-N 3-methylpyridine Chemical compound CC1=CC=CN=C1 ITQTTZVARXURQS-UHFFFAOYSA-N 0.000 claims description 6
- FKNQCJSGGFJEIZ-UHFFFAOYSA-N 4-methylpyridine Chemical compound CC1=CC=NC=C1 FKNQCJSGGFJEIZ-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 claims description 5
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 claims description 4
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- XNLICIUVMPYHGG-UHFFFAOYSA-N pentan-2-one Chemical compound CCCC(C)=O XNLICIUVMPYHGG-UHFFFAOYSA-N 0.000 claims description 4
- FDPIMTJIUBPUKL-UHFFFAOYSA-N pentan-3-one Chemical compound CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 claims description 4
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 claims description 3
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 claims description 3
- DVECBJCOGJRVPX-UHFFFAOYSA-N butyryl chloride Chemical compound CCCC(Cl)=O DVECBJCOGJRVPX-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 2
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims 2
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 abstract 1
- 150000008064 anhydrides Chemical class 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000007098 aminolysis reaction Methods 0.000 description 9
- 239000007787 solid Substances 0.000 description 8
- -1 anhydride compound Chemical class 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000725 suspension Substances 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 238000005917 acylation reaction Methods 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000010515 propionylation reaction Methods 0.000 description 4
- 230000015556 catabolic process Effects 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 239000012535 impurity Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 2
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 208000027866 inflammatory disease Diseases 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 150000003141 primary amines Chemical class 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 150000003335 secondary amines Chemical class 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GLAJUXBOZSWZMM-IDIDPBNYSA-N (6s,8s,9r,10s,11s,13s,14s,16r,17r)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,11,12,14,15,16-octahydrocyclopenta[a]phenanthrene-17-carbothioic s-acid Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(S)=O)(O)[C@@]2(C)C[C@@H]1O GLAJUXBOZSWZMM-IDIDPBNYSA-N 0.000 description 1
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- SVYKKECYCPFKGB-UHFFFAOYSA-N N,N-dimethylcyclohexylamine Chemical compound CN(C)C1CCCCC1 SVYKKECYCPFKGB-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229910052806 inorganic carbonate Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical class O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
- C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Pulmonology (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
Description
Framgangsmåte for esterifisering av en karbothiotisk syre Method for the esterification of a carbothiotic acid
Foreliggende oppfinnelse angår generelt en framgangsmåte for å esterifisere en karbothiotisk syre, særlig men ikke utelukkende, i framstillingen avfluticasone-propionat; og til bruk av enkelte mellomprodukt. The present invention generally relates to a process for esterifying a carbothioic acid, particularly but not exclusively, in the production of fluticasone propionate; and for the use of certain intermediate products.
I et aspekt angår foreliggende oppfinnelse en forbedret framgangsmåte for esterifisering av C-17 hydroksyl-gruppen av 6a,9a-difluor-llp,17a-dihydroksy-16a-metyl-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, forbindelse av formel [I], omfattende behandling av dette mellomproduktet med et lite overskudd av et acyl-klorid med den generelle formelen R-COCI, hvor R er - CH2CH3, -CH2CH2CH3eller -CH(CH3)2, i nærvær av et egnet tertiært amin, i et inert løsningsmiddel, ved en temperatur mellom 5°C og -20°C, for selektivt å oppnå 17a-acyl-derivatet av formel [II]. In one aspect, the present invention relates to an improved process for the esterification of the C-17 hydroxyl group of 6a,9a-difluoro-11p,17a-dihydroxy-16a-methyl-3-oxoandrostal-1,4-diene-17p-carbothioic acid, compound of formula [I], comprising treating this intermediate with a small excess of an acyl chloride of the general formula R-COCl, where R is -CH2CH3, -CH2CH2CH3 or -CH(CH3)2, in the presence of a suitable tertiary amine, in an inert solvent, at a temperature between 5°C and -20°C, to selectively obtain the 17a-acyl derivative of formula [II].
Denne oppfinnelsen framskaffer en esterifiserings-prosess som er enklere og mer økonomisk effektiv enn de som er omtalt i kjent teknikk, fordi den undertrykker en av de to kjemiske reaksjonene beskrevet i de prosessene. Et annet trekk med prosessen i samsvar med oppfinnelsen er at den gir 17a-estere med høy renhet. This invention provides an esterification process that is simpler and more economically efficient than those described in the prior art, because it suppresses one of the two chemical reactions described in those processes. Another feature of the process according to the invention is that it gives 17a-esters of high purity.
Mer spesifikt angår foreliggende oppfinnelse en forbedret framgangsmåte for framstilling av 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-propionyloksy-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, forbindelse av formel [III], som er et mellomprodukt i syntesen av fluticasone-propionat, en aktiv ingrediens benyttet som et anti-inflammatorisk steroid, effektivt for behandling av inflammatoriske sykdommer så som astma og kronisk obstruktiv lungesykdom. More specifically, the present invention relates to an improved process for the production of 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene-17p-carbothioic acid, compound of formula [III] , which is an intermediate in the synthesis of fluticasone propionate, an active ingredient used as an anti-inflammatory steroid, effective for the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease.
US patent 4,335,121, Britiske patenter GB 2,088,877, GB 2,137,206, US patent 4,578,221 og J. Med. Chem., 1994, 37, 3717-3729, beskriver 17a-propionyleringen av forbindelse [I], for å oppnå fluticasone-propionat mellomproduktet [III], gjennom de to kjemiske trinnene vist nedenfor, via den blandete anhydrid-forbindelsen [IV]. US Patent 4,335,121, British Patents GB 2,088,877, GB 2,137,206, US Patent 4,578,221 and J. Med. Chem., 1994, 37, 3717-3729, describes the 17a-propionylation of compound [I], to obtain the fluticasone propionate intermediate [III], through the two chemical steps shown below, via the mixed anhydride compound [IV].
I det første trinnet (a) ble det blandete anhydridet [IV] framstilt med et overskudd på i det minste 2 mol propionyl-klorid per mol forbindelse [I], in nærvær av trietylamin og ved bruk av diklormetan som løsningsmiddel. Ved avslutning av propionylerings-reaksjonen, ble reaksjons-blandingen opparbeidet og et mattgult fast stoff ble oppnådd. I det andre trinnet (b), ble dette faste stoffet løst i aceton og behandlet med dietylamin, for å konvertere det blandete anhydridet til forbindelse [III]. Så snart aminolyse-reaksjonen var fullstendig, ble reaksjons-blandingen opparbeidet for å isolere forbindelse [III]. In the first step (a), the mixed anhydride [IV] was prepared with an excess of at least 2 mol of propionyl chloride per mol of compound [I], in the presence of triethylamine and using dichloromethane as solvent. Upon completion of the propionylation reaction, the reaction mixture was worked up and a dull yellow solid was obtained. In the second step (b), this solid was dissolved in acetone and treated with diethylamine, to convert the mixed anhydride into compound [III]. As soon as the aminolysis reaction was complete, the reaction mixture was worked up to isolate compound [III].
Internasjonal patent søknad WO 03/066654 gjør krav på framstillingen av mellomproduktet [III] ved å: (a) reagere forbindelse [I] med i det minste 1,3 mol av et aktivert derivat av propionsyre per mol forbindelse [I], og fjerne av den svovel-forbundete delen fra enhver forbindelse av formel [IV] med et organisk primært eller sekundært amin så som dietanolamin eller N-metylpiperazin. International patent application WO 03/066654 claims the preparation of the intermediate [III] by: (a) reacting compound [I] with at least 1.3 mol of an activated derivative of propionic acid per mol of compound [I], and removing of the sulfur-linked moiety from any compound of formula [IV] with an organic primary or secondary amine such as diethanolamine or N-methylpiperazine.
Patentsøknad WO 01/62722 omtaler 17a-esterifiseringen av oksysyre-forbindelsen [V] med et alkanoyl-halid, i nærvær av en base, og spesielt beskrives framstillingen av 17a-propionat-forbindelsen av formel [VI] Patent application WO 01/62722 mentions the 17a-esterification of the oxyacid compound [V] with an alkanoyl halide, in the presence of a base, and in particular describes the preparation of the 17a-propionate compound of formula [VI]
ved å: (a) reagere oksysyren av formel [V] med 2,3 mol propionyl-klorid per mol forbindelse [V], ved bruk av trietylamin som base, og (b) in situ reagere forbindelsen oppnådd i (a) med dietylamin. by: (a) reacting the oxyacid of formula [V] with 2.3 moles of propionyl chloride per mole of compound [V], using triethylamine as base, and (b) in situ reacting the compound obtained in (a) with diethylamine .
Alle de 17a-acylerings-prosedyrene som er beskrevet i kjent teknikk, enten for den karbothiotiske syren [I] eller den beslektete karboksyliske syren [V], benytter et overskudd av den acylerende forbindelsen for å sikre komplettering av 17a-acyleringen, og krever dermed aminolyse, med et hensiktsmessig primært eller sekundært amin, av ethvert dannet blandet an hyd rid. All of the 17a-acylation procedures described in the prior art, either for the carbothioic acid [I] or the related carboxylic acid [V], use an excess of the acylating compound to ensure completion of the 17a-acylation, thus requiring aminolysis, with an appropriate primary or secondary amine, of any mixed anhydride formed.
Det er nå funnet at transformasjonen av den karbothiotiske syre-forbindelsen [I] til forbindelsene av den generelle formel [II], kan selektivt forekomme direkte, med neglisjerbar dannelse av det tilsvarende blandete anhydridet, under forhold som er beskrevet her. Ved å følge framgangsmåten i samsvar med foreliggende oppfinnelse, blir mellomproduktet 6a,9a-difluor-llp,17a-dihydroksy-16a-metyl-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, forbindelse [I], direkte konvertert til forbindelser med den generelle formelen [II] It has now been found that the transformation of the carbothioic acid compound [I] to the compounds of the general formula [II] can selectively occur directly, with negligible formation of the corresponding mixed anhydride, under conditions described herein. By following the procedure in accordance with the present invention, the intermediate 6a,9a-difluoro-11p,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17p-carbothioic acid, compound [I], is directly converted to compounds of the general formula [II]
ved reaksjon med et lite overskudd av det tilsvarende acyl-kloridet, i et inert løsningsmiddel, i nærvær av et egnet tertiært amin. by reaction with a small excess of the corresponding acyl chloride, in an inert solvent, in the presence of a suitable tertiary amine.
Den spesifikke fordelen med foreliggende oppfinnelse i forhold til de i kjent teknikk, er at forbindelsene av den generelle formelen [II] oppnås direkte fra forbindelse [I], uten behov for å utføre aminolyse av det tilsvarende blandete anhydridet. I tillegg, under aminolyse-forholdene beskrevet i kjent teknikk, er den kjemiske stabiliteten av karbothiotisk-syre derivater, så som forbindelse [III], begrenset, derfor gir den forenklete prosessen i samsvar med foreliggende oppfinnelsen 17a-estere med høyere renhet, ved å eliminere aminolyse-reaksjonen. The specific advantage of the present invention compared to those in the prior art is that the compounds of the general formula [II] are obtained directly from compound [I], without the need to carry out aminolysis of the corresponding mixed anhydride. In addition, under the aminolysis conditions described in the prior art, the chemical stability of carbothioic acid derivatives, such as compound [III], is limited, therefore the simplified process according to the present invention gives 17a-esters of higher purity, by eliminate the aminolysis reaction.
I samsvar med foreliggende oppfinnelse, er det framskaffet en framgangsmåte for å framstille forbindelser av formelen [II] In accordance with the present invention, a process has been provided for preparing compounds of the formula [II]
ved esterifisering av C-17 hydroksyl-gruppen av 6a,9a-difluor-llp,17a-dihydroksy-16a-metyl-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, forbindelse av formel [I], idet framgangsmåten omfatter behandling av forbindelse [I] med et lite overskudd av et acyl-klorid av den generelle formelen R-COCI, hvor R representerer-CH2CH3, -CH2CH2CH3eller-CH(CH3)2,i et inert løsnings-middel, i nærvær av et tertiært amin. Prosessen utføres fortrinnsvis ved en temperatur på fra 5°C til -20°C. by esterification of the C-17 hydroxyl group of 6a,9a-difluoro-11p,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17p-carbothioic acid, compound of formula [I], the method being comprises treating compound [I] with a small excess of an acyl chloride of the general formula R-COCl, where R represents -CH2CH3, -CH2CH2CH3 or -CH(CH3)2, in an inert solvent, in the presence of a tertiary amine. The process is preferably carried out at a temperature of from 5°C to -20°C.
Oppfinnelsen framskaffer også bruk av forbindelser av formel [II] når de framstilles i samsvar med framgangsmåten av oppfinnelsen, for framstilling av terapeutisk nyttige medikamenter. The invention also provides for the use of compounds of formula [II] when prepared in accordance with the method of the invention, for the preparation of therapeutically useful medicaments.
Foreliggende oppfinnelse framskaffet en forbedret og forenklet framgangsmåte for den selektive 17a-esterifiseringen av forbindelsen [I], som danner neglisjerbare mengder av blandete anhydrider med den generelle formelen [VII] The present invention provided an improved and simplified procedure for the selective 17a-esterification of the compound [I], which forms negligible amounts of mixed anhydrides of the general formula [VII]
hvor R representerer -CH2CH3, -CH2CH2CH3eller-CH(CH3)2, uten behov for å utføre aminolyse-reaksjon på de tilsvarende blandete hydrolysene. Framgangsmåten omfatter reaksjonen av forbindelse [I], 6a,9a-difluor-llp,17a-dihydroksy-16a-metyl-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, med et lite overskudd av en acyl-klorid med den generelle formelen R-COCI, hvor R representerer CH2CH3, -CH2CH2CH3eller - CH(CH3)2;i nærværet av et egnet organisk tertiært amin, i et inert løsningsmiddel, for å gi forbindelsene av den generelle formelen [II] where R represents -CH2CH3, -CH2CH2CH3 or -CH(CH3)2, without the need to carry out the aminolysis reaction on the corresponding mixed hydrolyses. The process comprises the reaction of compound [I], 6α,9α-difluoro-11β,17α-dihydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioic acid, with a small excess of an acyl chloride with of the general formula R-COCl, where R represents CH2CH3, -CH2CH2CH3 or - CH(CH3)2; in the presence of a suitable organic tertiary amine, in an inert solvent, to give the compounds of the general formula [II]
hvor R representerer -CH2CH3, -CH2CH2CH3or -CH(CH3)2. where R represents -CH2CH3, -CH2CH2CH3 or -CH(CH3)2.
En særlig foretrukket utførelse av den foreliggende oppfinnelsen for å framskaffe en forbedret framgangsmåte for framstilling av 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-propionyloksy-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, forbindelse av formel [III], omfatter å reagere 6a,9a-difluor-llp,17a-dihydroksy-16a-metyl-3-oxoandrosta-l,4-diene-17p-karbothiotisksyre [II] med et lite overskudd av propionyl-klorid, i nærvær av et egnet tertiært amin, i et inert løsnings-middel. A particularly preferred embodiment of the present invention to provide an improved process for the production of 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrostal-1,4-diene-17p-carbothioic acid, compound of formula [III], comprises reacting 6a,9a-difluoro-11p,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17p-carbothioic acid [II] with a small excess of propionyl chloride , in the presence of a suitable tertiary amine, in an inert solvent.
Forbindelsen av formel [III] er et kjent mellomprodukt nyttig i framstillingen av anti-inflammatoriske steroider så som fluticasone-propionat av formel [A] (beskrevet i US 4 335 121), sp, er svært effektivt i behandlingen av inflammatoriske sykdommer så som astma og kronisk obstruktiv lungesykdom (COPD), og i framstillingen av den relaterte 6a,9a-difluor-llp-hydroksy- 16a-metyl-3-oxo-17a-propionyloksy-androsta-l,4-diene-17p-karbothiotisk syre S-(2-oxo-tetrahydro-furan-3-yl) esteren av formel [B] (beskrevet i søknad WO 97/24365), som innehar nyttig anti-inflammatorisk aktivitet og har lite eller ingen systemisk aktivitet. The compound of formula [III] is a known intermediate useful in the preparation of anti-inflammatory steroids such as fluticasone propionate of formula [A] (described in US 4,335,121), sp, is highly effective in the treatment of inflammatory diseases such as asthma and chronic obstructive pulmonary disease (COPD), and in the production of the related 6a,9a-difluoro-11p-hydroxy-16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17p-carbothioic acid S- (2-oxo-tetrahydro-furan-3-yl) ester of formula [B] (described in application WO 97/24365), which possesses useful anti-inflammatory activity and has little or no systemic activity.
Følgelig framskaffer oppfinnelsen også en framgangsmåte for å framstille fluticasone-propionat, idet framgangsmåten omfatter framstilling av 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-propionyloxy-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre i samsvar med framgangsmåten av oppfinnelsen og konvertering av forbindelsen til fluticasone-propionat. Accordingly, the invention also provides a process for producing fluticasone propionate, the process comprising the production of 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene-17p-carbothioic acid in accordance with the process of the invention and converting the compound to fluticasone propionate.
Det er også framskaffet en framgangsmåte for framstilling av 6a -9a -difluor-llp-hydroksy-16a -metyl-3-oxo-17a-propionyloxy-androsta-l,4-diene-17p-karbothiotisk syre S-(2-oxo-tetrahydrofuran-3-yl) ester, idet framgangsmåten omfatter framstilling av 6a, 9a-difluor-llp-hydroksy-16a-metyl-17a-propionyloxy-3-oxoandrosta-l,4-diene-17p-karbothiotisksyre i samsvar med framgangsmåten av oppfinnelsen, og konvertering av forbindelsen til den nevnte S-esteren. A process for the production of 6a -9a -difluoro-11p-hydroxy-16a -methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17p-carbothioic acid S-(2-oxo- tetrahydrofuran-3-yl) ester, the method comprising the production of 6a, 9a-difluoro-11p-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene-17p-carbothioic acid in accordance with the method of the invention , and converting the compound into said S-ester.
Den foreliggende oppfinnelsen framskaffer en fordelaktig framgangsmåte for framstillingen av 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-propionyloxy-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, forbindelse av formel [III] omfattende behandling av forbindelsen [I], 6a,9a-difluor-llp,17a-dihydroksy-16a-metyl-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, med et lite overskudd av propionyl-klorid, i nærvær av et egnet tertiært amin, i et inert løsningsmiddel, ved en temperatur mellom 5°C og -20°C. The present invention provides an advantageous process for the production of 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene-17p-carbothioic acid, compound of formula [III] comprising treatment of the compound [I], 6a,9a-difluoro-11p,17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17p-carbothioic acid, with a small excess of propionyl chloride, in the presence of a suitable tertiary amine, in an inert solvent, at a temperature between 5°C and -20°C.
Acyl-kloridet med den generelle formelen R-COCI blir fortrinnsvis benyttet i framgangsmåten av foreliggende oppfinnelse i et molart forhold fra 1,0 til 1,2 mol acyl-klorid per mol utgangs-forbindelse [I], fortrinnsvis i en mengde innen dette området. The acyl chloride with the general formula R-COCI is preferably used in the method of the present invention in a molar ratio of from 1.0 to 1.2 mol of acyl chloride per mol of starting compound [I], preferably in an amount within this range .
Inerte løsningsmidler for 17a-acylerings-framgangsmåten for den foreliggende oppfinnelsen inkluderer aceton, tetrahydrofuran, dimetylacetamid, diklormetan, etyl-acetat, 2-pentanon, 3-pentanon, 4-metyl-2-pentanon og 2-butanon. Aceton er det foretrukne løsningsmidlet. Inert solvents for the 17α-acylation process of the present invention include acetone, tetrahydrofuran, dimethylacetamide, dichloromethane, ethyl acetate, 2-pentanone, 3-pentanone, 4-methyl-2-pentanone and 2-butanone. Acetone is the preferred solvent.
Egnete tertiære aminer for å utføre den selektive 17a-propionyleringen inkluderer pyridin, 2-picolin 3-picolin, 4-picolin, N-metylimidazol, og N-metylpyrrolidin. Suitable tertiary amines for carrying out the selective 17α-propionylation include pyridine, 2-picoline, 3-picoline, 4-picoline, N-methylimidazole, and N-methylpyrrolidine.
17a-acylerings-reaksjonen i samsvar med oppfinnelsen blir fortrinnsvis utført ved en temperatur mellom 5°C og -20°C. The 17a-acylation reaction in accordance with the invention is preferably carried out at a temperature between 5°C and -20°C.
Bruken av de tertiære aminene definert ovenfor, som hensiktsmessig for framgangsmåten i samsvar med patentet, presenterer fordeler i forhold til andre baser tidligere beskrevet i kjent teknikk, så som trietylamin, tripropylamin, etyldiisopropylamin, N,N-dimetylaniline, N,N-dimetyl-sykloheksylamin, uorganiske karbonater så som, f.eks. natriumhydrogen-karbonat, kalium-karbonat og natrium-karbonat. Ved bruk av disse basene unngås dannelsen av høye nivå av den blandete anhydrid-forbindelsen [IV] eller ufullstendig forbruk av forbindelse [I] eller dannelsen av høyt nivå urenheter, hvilket er tilfellet når natrium-hydrogen-karbonat benyttes. The use of the tertiary amines defined above, as appropriate for the process in accordance with the patent, presents advantages over other bases previously described in the prior art, such as triethylamine, tripropylamine, ethyldiisopropylamine, N,N-dimethylaniline, N,N-dimethyl- cyclohexylamine, inorganic carbonates such as, e.g. sodium hydrogen carbonate, potassium carbonate and sodium carbonate. Using these bases avoids the formation of high levels of the mixed anhydride compound [IV] or incomplete consumption of compound [I] or the formation of high levels of impurities, which is the case when sodium hydrogen carbonate is used.
Under de foretrukne forholdene av den foreliggende oppfinnelsen, går 17a-esterifisering til komplettering med 1,0 til 1,2 mol propionyl-klorid per mol forbindelse [I], i nærvær av pyridin, og nivåene av blandet anhydrid funnet under reaksjonen er under 3% (i area, ved HPLC). Med disse lave nivåene av blandet anhydrid, er ikke aminolyse-reaksjonen påkrevd, og forbindelse [III] isoleres med en høy grad av renhet, ved opparbeidelse av propionylerings-reaksjonen. Under the preferred conditions of the present invention, 17a-esterification proceeds to completion with 1.0 to 1.2 moles of propionyl chloride per mole of compound [I], in the presence of pyridine, and the levels of mixed anhydride found during the reaction are below 3 % (in area, by HPLC). With these low levels of mixed anhydride, the aminolysis reaction is not required, and compound [III] is isolated with a high degree of purity, by working up the propionylation reaction.
Under forholdene beskrevet i kjent teknikk, når forbindelse [III] blir framstilt via det blandete anhydridet, kan delvis degradering av forbindelse [III] forekomme under aminolyse-reaksjonen. Denne degraderingen er særlig problematisk når forlenget reaksjons-tid forekommer, hvilket er forventet i industriell skala. Under forholdene som er beskrevet i den foreliggende oppfinnelsen, unngås denne in situ degraderingen av forbindelse [III]. Under the conditions described in the prior art, when compound [III] is prepared via the mixed anhydride, partial degradation of compound [III] may occur during the aminolysis reaction. This degradation is particularly problematic when extended reaction time occurs, which is expected on an industrial scale. Under the conditions described in the present invention, this in situ degradation of compound [III] is avoided.
Det er funnet at ved å følge kjent teknikk, dannes en forløper (G forløper) til en urenhet (urenhet G). It has been found that by following the known technique, a precursor (G precursor) to an impurity (impurity G) is formed.
Med framgangsmåten i samsvar med den foreliggende oppfinnelsen, dannes dimer G ved nivå under 0,3%, dimer G er vanskelig å fjerne fra det endelige produktet, fluticasone-propionat, ved rekrystallisering når nivåene er høyere enn 0,5%, Dermed unngås gjentatte rekrystalliseringer for å oppnå material av den nødvendige renhet, hvilket betydelig reduserer det totale utbyttet. With the process according to the present invention, dimer G is formed at levels below 0.3%, dimer G is difficult to remove from the final product, fluticasone propionate, by recrystallization when levels are higher than 0.5%, thus avoiding repeated recrystallizations to obtain material of the required purity, which significantly reduces the overall yield.
En annen utførelse av denne oppfinnelsen framskaffer en forbedret framgangsmåte for framstilling av forbindelsene 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-butyryloxy-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre, forbindelse av formel [VIII] og 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-isobutyryloksy-3-oxoandrosta-l,4-diene-17p-karbothiotisk syre av formel [IX]. Forbindelser av formel [VIII] og [IX] er direkte framstilt fra forbindelse [I] ved reaksjon med et lite overskudd av det tilsvarende acyl-klorid, uten behov for å utføre en aminolyse-reaksjon av de tilsvarende blandete anhydridene. Another embodiment of this invention provides an improved process for the preparation of the compounds 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-butyryloxy-3-oxoandrostal-1,4-diene-17p-carbothioic acid, compound of formula [VIII] and 6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-isobutyryloxy-3-oxoandrosta-1,4-diene-17β-carbothioic acid of formula [IX]. Compounds of formula [VIII] and [IX] are directly prepared from compound [I] by reaction with a small excess of the corresponding acyl chloride, without the need to carry out an aminolysis reaction of the corresponding mixed anhydrides.
I samsvar med et foretrukket aspekt av den foreliggende oppfinnelsen, er esterifisering av forbindelse [I] for å oppnå forbindelse [VIII], utført med 1,0 til 1,2 mol butyryl-klorid, i aceton, i nærvær av pyridin, ved en temperatur mellom 5°C og -20°C, fortrinnsvis mellom 5°C og 0°C. Esterifiseringen av forbindelse [I] for å oppnå forbindelse [IX] er fortrinnsvis utført med 1,0 til 1,2 mol isobutyryl-klorid, i aceton, i nærvær av pyridin, ved en temperatur mellom 5°C og-20°C, fortrinnsvis mellom 5°C og 0°C. In accordance with a preferred aspect of the present invention, esterification of compound [I] to obtain compound [VIII] is carried out with 1.0 to 1.2 mol of butyryl chloride, in acetone, in the presence of pyridine, at a temperature between 5°C and -20°C, preferably between 5°C and 0°C. The esterification of compound [I] to obtain compound [IX] is preferably carried out with 1.0 to 1.2 mol of isobutyryl chloride, in acetone, in the presence of pyridine, at a temperature between 5°C and -20°C, preferably between 5°C and 0°C.
De følgende eksemplene illustrerer oppfinnelsen og enkelte foretrukne utførelser og er unntatt for begrensende karakter for ramma for oppfinnelsen. The following examples illustrate the invention and some preferred embodiments and are exempt from the limiting nature of the scope of the invention.
Eksempel 1: Framstilling av 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-propionyloxy-3-oxoandrosta-l,4-diene-17p-karbothiotisksyre Example 1: Preparation of 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene-17p-carbothioic acid
En suspensjon av forbindelse [I] (10 g, 0,024 mol) i aceton (175 ml) ble avkjølt til 20°C og behandlet med pyridin (30 ml) og propionyl-klorid (2,3 ml, 0,026 mol), mens temperaturen ble holdt mellom 20°C og 15°C. Blandingen ble rørt ved-20°C/-15°C inntil reaksjonen var fullstendig. En andre tilsats av propionyl-klorid (0,02 ml) kan utføres om nødvendig for å komplettere reaksjonen. Forbindelse [III] felles ut ved tilsats av vann (240 ml) og konsentrert saltsyre (30 ml). Suspensjonen ble rørt i 2 timer ved en temperatur mellom 0°C og 5°C, filtrert, og den våte kaken ble vasket med kaldt vann inntil nøytral pH. Det faste stoffet ble tørket ved en temperatur under 40°C, under vakuum, for å gi tittel-forbindelsen som et hvitt til off-white fast stoff (10,04 g; 88%; Renhet, areal % ved HPLC: 96,1%). A suspension of compound [I] (10 g, 0.024 mol) in acetone (175 mL) was cooled to 20 °C and treated with pyridine (30 mL) and propionyl chloride (2.3 mL, 0.026 mol), while the temperature was kept between 20°C and 15°C. The mixture was stirred at -20°C/-15°C until the reaction was complete. A second addition of propionyl chloride (0.02 ml) can be carried out if necessary to complete the reaction. Compound [III] precipitates out by adding water (240 ml) and concentrated hydrochloric acid (30 ml). The suspension was stirred for 2 hours at a temperature between 0°C and 5°C, filtered, and the wet cake was washed with cold water until neutral pH. The solid was dried at a temperature below 40°C, under vacuum, to give the title compound as a white to off-white solid (10.04 g; 88%; Purity, Area % by HPLC: 96.1 %).
Eksempel 2: Framstilling av 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-isobutyryloksy-3-oxoandrosta-l,4-diene-17p-karbothiotisksyre Example 2: Preparation of 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-isobutyryloxy-3-oxoandrosta-1,4-diene-17p-carbothioic acid
Isobutyryl-klorid (0,28 ml, 0,0027 moles) ble sakte satt til en blanding av aceton (17,5 ml), forbindelse [I] (1 g, 0,0024 mol) og pyridin (3 ml), ved temperaturer mellom 5°C og 0°C, og blandingen ble rørt ved det temperatur-området inntil forbindelse [I] var brukt opp. Ved komplettering av reaksjonen ble tittel-forbindelsen felt ut ved tilsats av vann (24 ml) og konsentrert saltsyre (3 ml). Suspensjonene ble rørt i 1 til 2 timer, ved en temperatur mellom 0°C og 5°C, filtrert, og den våte kaken ble vasket med kaldt vann inntil nøytral pH. Det våte faste stoffet ble tørket ved en temperatur lavere enn 40°C, under vakuum, for å gi tittel-forbindelsen som et hvitt til off-white fast stoff (1,09 g; 93%; Renhet, areal % ved HPLC: 94,8%). Isobutyryl chloride (0.28 mL, 0.0027 moles) was slowly added to a mixture of acetone (17.5 mL), compound [I] (1 g, 0.0024 mole) and pyridine (3 mL), at temperatures between 5°C and 0°C, and the mixture was stirred at that temperature range until compound [I] was used up. Upon completion of the reaction, the title compound was precipitated by the addition of water (24 ml) and concentrated hydrochloric acid (3 ml). The suspensions were stirred for 1 to 2 hours, at a temperature between 0°C and 5°C, filtered, and the wet cake was washed with cold water until neutral pH. The wet solid was dried at a temperature lower than 40°C, under vacuum, to give the title compound as a white to off-white solid (1.09 g; 93%; Purity, Area % by HPLC: 94 .8%).
Eksempel 3: Framstilling av 6a,9a-difluor-llp-hydroksy-16a-metyl-17a-propionyloxy-3-oxoandrosta-l,4-diene-17p-karbothiotisksyre Example 3: Preparation of 6a,9a-difluoro-11p-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene-17p-carbothioic acid
En suspensjon av forbindelse [I] (1 g, 0,0024 mol) i aceton (17 ml) ble avkjølt til en temperatur mellom -20°C og-15°C. N-metylimidazol (2,9 ml) og propionyl-klorid (0,23 ml, 0,0026 mol) ble sekvensielt satt til løsningen, mens temperaturen mellom-20°C og 15°C ble opprettholdt. Ved komplettering av reaksjonen, ble forbindelse [III] felt ut ved tilsats av vann (24 ml) og konsentrert saltsyre (3 ml). Suspensjonen ble rørt i 2 timer ved ca 0°C, filtrert, og den våte kaken ble vasket med kaldt vann inntil nøytral pH. Det våte faste stoffet ble tørket ved en temperatur under 40°C, under vakuum, for å gi tittel-forbindelsen som et hvitt til off white fast stoff (1,0 g; 88%; Renhet, areal % ved HPLC: 96,8%). A suspension of compound [I] (1 g, 0.0024 mol) in acetone (17 ml) was cooled to a temperature between -20°C and -15°C. N-methylimidazole (2.9 mL) and propionyl chloride (0.23 mL, 0.0026 mol) were sequentially added to the solution while maintaining the temperature between -20°C and 15°C. Upon completion of the reaction, compound [III] was precipitated by addition of water (24 mL) and concentrated hydrochloric acid (3 mL). The suspension was stirred for 2 hours at about 0°C, filtered, and the wet cake was washed with cold water until neutral pH. The wet solid was dried at a temperature below 40°C, under vacuum, to give the title compound as a white to off white solid (1.0 g; 88%; Purity, Area % by HPLC: 96.8 %).
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| PCT/GB2004/005052 WO2006043015A1 (en) | 2004-10-19 | 2004-12-02 | Process for the esterification of a carbothioic acid |
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| CA2241728A1 (en) | 1995-12-29 | 1997-07-10 | Panayiotis Alexandrou Procopiou | Lactone derivatives of 17.beta.-carboxy, carbothio and amide androstane derivatives |
| US20020133032A1 (en) | 2000-02-25 | 2002-09-19 | Jufang Barkalow | Method for the preparation of fluticasone and related 17beta-carbothioic esters using a novel carbothioic acid synthesis and novel purification methods |
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- 2004-12-02 US US11/577,462 patent/US9670246B2/en active Active
- 2004-12-02 AT AT04822330T patent/ATE482967T1/en not_active IP Right Cessation
- 2004-12-02 WO PCT/GB2004/005052 patent/WO2006043015A1/en active Application Filing
- 2004-12-02 NZ NZ554865A patent/NZ554865A/en not_active IP Right Cessation
- 2004-12-02 DE DE602004029402T patent/DE602004029402D1/en active Active
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2007
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Also Published As
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|---|---|
| CN101065394B (en) | 2012-11-14 |
| ZA200703257B (en) | 2009-06-24 |
| NO20071996L (en) | 2007-07-06 |
| WO2006043015B1 (en) | 2006-11-09 |
| PT103202B (en) | 2011-01-27 |
| JP5030783B2 (en) | 2012-09-19 |
| CA2584052A1 (en) | 2006-04-27 |
| EP1802647B1 (en) | 2010-09-29 |
| PL214247B1 (en) | 2013-07-31 |
| US9670246B2 (en) | 2017-06-06 |
| US20070287846A1 (en) | 2007-12-13 |
| ATE482967T1 (en) | 2010-10-15 |
| NZ554865A (en) | 2009-03-31 |
| AU2004324237B2 (en) | 2011-10-20 |
| DE602004029402D1 (en) | 2010-11-11 |
| CA2584052C (en) | 2012-03-13 |
| RU2351605C2 (en) | 2009-04-10 |
| IL182638A0 (en) | 2007-07-24 |
| ES2353129T3 (en) | 2011-02-25 |
| RU2007118654A (en) | 2008-11-27 |
| EP1802647A1 (en) | 2007-07-04 |
| IL182638A (en) | 2012-03-29 |
| PL382970A1 (en) | 2008-02-04 |
| WO2006043015A1 (en) | 2006-04-27 |
| AU2004324237A1 (en) | 2006-04-27 |
| SI1802647T1 (en) | 2011-01-31 |
| CN101065394A (en) | 2007-10-31 |
| JP2008517044A (en) | 2008-05-22 |
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